THIS WEEK CD 74 : receptive to survival

نویسنده

  • Michael J. Haas
چکیده

Researchers at the Weizmann Institute of Science have described an antiapoptotic signaling pathway in murine B cells that is triggered by activation of the macrophage migration inhibitor factor receptor, also called CD74. The work elucidates the mechanism of action of Immunomedics Inc.’s IMMU-110 and milatuzumab, as well as other drug candidates targeting the MIF receptor. And by delineating the downstream signaling cascade, the study also may yield new therapeutic targets for certain cancers. Immunomedics has been working on antibodies against CD74 since early 2000 based on preclinical studies in human cancer cell lines and tumor xenografts in mice. Genmab A/S also has preclinical antibodies against CD74. But until now, the way that this cell-surface receptor exerts its effects has been poorly understood. Indeed, it was only in 2003 that studies in human cell lines confirmed that CD74 is the primary site of action for MIF, one of the earliest cytokines discovered1,2. MIF has been shown to stimulate an immune response in the presence of steroids and other immune suppressants. It plays a role in the cytokine cascades involved in certain inflammatory diseases and inhibits the activity of the tumor suppressor p53. In animal studies, antibodies that neutralize MIF have provided beneficial effects in arthritis, septic shock, cancer, glomerulonephritis and colitis. MIF has proved to be a difficult target because of the problems involved in inhibiting its proinflammatory function. Nevertheless, a number of companies have compounds targeting MIF in preclinical development. Novartis AG in-licensed AVP 28225 for use in inflammatory diseases from Avanir Pharmaceuticals3, which has a screening assay to identify small molecules believed to effectively block MIF’s biological activity. Baxter International Inc. and Dyax Corp. are developing mAbs against the target; and Cytokine PharmaSciences Inc. licensed rights to antibody neutralization of the target to Baxter but retained the right to develop small molecule inhibitors of MIF. Before it was identified as the MIF receptor, CD74 was thought to function primarily as a chaperone for intracellular processes that lead to the antigen-presenting behavior of B cells. The latest work, published in the Sept. 10 issue of Blood by Idit Shachar and colleagues at Weizmann, describes a study in murine B cells that identifies the specific molecules involved in the MIF/CD74 signaling pathway that modulates B cell survival4. ANALYSIS

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تاریخ انتشار 2008